Chemical methods

ABSTRACT

This invention relates to a method for N-demethylating an N-methyl morphinane comprising the steps of: (i) treating said N-methyl morphinane with an oxidizing agent to form the N-oxide morphinane; and (ii) treating said N-oxide morphinane with a reducing agent. This invention also relates to a method for oxidizing a Δ 7 -morphinane compound to a Δ 6 , Δ 8 -morphinane compound, comprising the steps of treating said Δ 7 -morphinane with γ-MnO 2  for a time and under conditions sufficient to oxidize said Δ 7 morphinane, and treating the γ-MnO 2  with glycol or a derivative thereof, and/or an inorganic salt.

[0001] The present invention relates generally to synthetic methods forthe production of opiate alkaloids, particularly morphinane compounds.More specifically, the invention relates to methods for demethylatingN-methyl morphinane compounds and to methods for introducing a 6,8-dienesystem into morphinane compounds.

[0002] The opiate alkaloids, obtained from poppy plants of the familyPapaveraceae, include some of the most powerfully acting and clinicallyuseful drugs in the depression of the central nervous system. Exemplaryopiates include, morphine (1), codeine (2), thebaine (3) and oripavine(4).

[0003] The fundamental ring system common to each of these compounds isthe morphinane skeleton, depicted in formula (A). Compounds containingthis skeleton are collectively referred to herein as morphinanes.

[0004] Morphine and codeine are principally used as analgesics but alsofind use as agents for inducing sleep in the presence of pain, easingdyspnea and as an anti-tussive. Despite its valuable clinicalproperties, morphine has a number of negative aspects as it alsodepresses respiration and increases the activity and the tone of thesmooth muscles of the gastrointestinal, biliary and urinary tractscausing constipation, gallbladder spasm and urinary retention. Inaddition, if administered to a patient over a period of time, thepatient develops a tolerance to the analgesic effect so that the dosagemust be increased to obtain the same level of pain relief. Incombination with the euphoric effect it exerts, physical dependence onmorphine and related compounds can develop.

[0005] Extensive efforts have been directed towards the semi-synthesisof second generation morphine-like molecules which retain the analgesicproperties but avoid the undesirable addictive side effects. Forexample, replacement of the N-methyl group of morphine with an N-allylgroup provides nalorphine which acts as a narcotic antagonist to reversemany of the undesirable side effects of morphine. Substitution of othergroups such as methallyl, propyl, isobutyl, propargyl or cyclopropargyl,methylcyclopropyl, and methylcyclobutyl also produce substances that areantagonists. Other second generation derivatives of natural opiatesinclude the 14-hydroxy opiate antagonists, exemplified by naltrexone (5)and naloxone (6), and the orvinols, exemplified by buprenorphine (7).

[0006] The industrial preparation of these second generation compoundsfrom the naturally occurring opiates alkaloids presents some common butchallenging problems. One problem common to the synthesis of many ofthese compounds is the removal of N-methyl substituent present innaturally occurring opiate starting materials such as morphine, codeine,thebaine and oripavine. A second problem common to any syntheticapproach to the 14-hydroxy opiates and the orvinols where the startingmaterials are Δ⁷-compounds, ie those having a double bond at the7-position (eg morphine and codeine) is the introduction of a 6,8-dienesystem, which is present in thebaine and oripavine. The incorporation ofa 6,8-diene system to produce Δ⁶,Δ⁸-morphinanes is a particularlyimportant step since it is the 6,8-diene that is oxidised during theincorporation of the 14-hydroxy group in the synthesis of 14-hydroxyopiates and the diene system is involved in a Diels-Alder reaction withan appropriate dienophile in the synthesis of orvinols.

[0007] N-Demethylation of tertiary amines was traditionally achievedusing cyanogen bromide in the von Braun reaction (von Braun, J Chem.Ber. 1990, 33, 1438). Limited yields and the toxicity of cyanogenbromide have seen this reaction largely replaced by chloroformatereagents (Cooley, J. H.; Evian, E. J. Synthesis, 1989, 1). Certainchloroformates, such as vinyl chloroformate, generally N-demethylate inhigh yield and the resultant carbamates are readily cleaved to affordthe corresponding secondary amines. Unfortunately this reagent is veryexpensive, and thus, its applicability to larger scale processes islimited. Some photochemical procedures have been developed for thecleavage of N-methyl amines (Lidner, J. H. E.; Kuhn, H. J.: Gollnick, K.Tetrahedron Lett. 172, 1705, Santamaria, J.: Ouchabane, R.: Rigaudy, J.Tetrahedron Lett. 1989, 30, 2927, Lopez, D.; Quinoa, E.; Riguera, R.Tetrahedron Lett. 1994, 35, 5727), but these methods have not seenwidespread use.

[0008] Due to their greater natural abundance, morphine and codeine arethe most desirable starting materials for the semi-synthetic approachesto second generation derivatives. However, these compounds do notpossess 6,8-diene system necessary for the preparation of secondgeneration morphinanes such as the 14-hydroxy opiates and the orvinols.It is therefore necessary to develop methods for the installation of the6,8-diene system. One method for forming the diene was reported byBarber and Rapoport in 1975 (Barber, R. B., Rapoport, H. J. Med. Chem.1975, 18, 1074). In this method, codeine was methylated to affordcodeine methyl ether (CME) which was further oxidised (by γ-MnO₂) tothebaine. The γ-MnO₂ oxidation was reported to proceed in 80% yield,giving an overall yield of 67% from codeine. This method required theuse of 25 molar equivalents of γ-MnO₂ and was conducted intetrahydrofuran under an atmosphere of nitrogen. However, such a highyield of thebaine via this methodology could not be reproduced by theinventors of the present invention and it is postulated that thebainemay be strongly adsorbing to the surface of the MnO₂ particles and thatthe use of such a large excess of oxidising agent used in thismethodology makes isolation of thebaine extremely difficult. Morerecently another procedure for the conversion of codeine to thebaine wasreported by Coop and Rice (Coop, A.; Rice, K. C. Heterocycles, 1998, 49,43) In this case, codeine was first oxidised to codeinone via anOppenhauer oxidation. Codeinone was then enolised and methylated usingMe₂SO₄. A range of conditions were evaluated for the enolisation stepand t-BuOK in the presence of a crown ether (18-crown-6) at 0° C. wasfound to give the best results (57% yield of thebaine). However, the useof strong bases such as potassium tert-butoxide and expensive crownethers to achieve a modest yield is non-ideal for a commercial process.

[0009] Thus, there remains a continued need for methods which canprovide access to N-demethylmorphinanes and morphinanes which have the6,8-diene system and to further second generation analogues such as14-hydroxy opiates and orvinols. New methods for the N-demethylation ofmorphinanes and the introduction of a 6,8-diene system have now beendeveloped.

[0010] Accordingly, in a first aspect, the present invention provides amethod for N-demethylating an N-methyl morphinane comprising the stepsof:

[0011] (i) treating said N-methyl morphinane with an oxidising agent toform the N-oxide morphinane; and

[0012] (ii) treating said N-oxide morphinane with a reducing agent.

[0013] It will be recognised that the oxidative and reductive steps mayalso affect other substituents of the morphinane, such as hydroxygroups. Thus, it is usually desirable to first protect the hydroxygroups with a protecting group which may optionally be removed after thedemethylation steps are completed. Protecting groups, which may betemporary or permanent, are known in the art and methods for theirinstallation and removal are described in standard references such asProtective Groups in Organic Synthesis, T. W. Greene and P Wutz, JohnWiley and Son, 2^(nd) Edition (1991). Exemplary hydroxy protectinggroups include C₁₋₆alkyl (including straight, branched and cyclicisomers of methyl, ethyl, propyl, butyl, pentyl and hexyl), aryl (egphenyl), benzyl, acyl (eg C(O)C₁₋₆alkyl, wherein alkyl is as describedabove) and silyl groups. Preferred hydroxy protecting groups includemethyl, ethyl, propyl, benzyl, and acetyl. Other groups which may alsorequire protection are keto groups. These may be protected for exampleas acetals. Other suitable protecting groups for ketones are also adescribed in Greene and Wutz supra. A morphinane compound which has hada hydroxy or keto group protected is referred to herein as a protectedmorphinane.

[0014] N-methyl morphinanes, protected derivatives, where appropriate,of which can be subjected to the demethylation treatment of theinvention, include those of the formula (i) or (ii) or (iii):

[0015] wherein

[0016] R and R¹ are independently a hydroxy, methoxy or ethoxy group

[0017] R² and R³ together form a carbonyl or a ═CH₂ group, R⁴ ishydrogen and

[0018] R⁵ is hydrogen or a hydroxy group and

[0019] is an optional double bond; or

[0020] R² is methoxy or hydroxy, R³ and R⁵ together form an ethylene orethenyl group and R⁴ is a hydroxy or keto-substituted straight orbranched C₁₋₆ alkyl group.

[0021] Examples of N-methyl morphinanes which may be demethylated inaccordance with the present invention include (where appropriate)protected derivatives of: morphine, codeine, codeine methyl ether, ethylmorphine (dionine), thebaine, oripavine, oxymorphone, heroin, 14-hydroxycodeinone, dihydrocodone, oxycodone, pholcodeine, etorphine,dihydromorphine, hydromorphone, hydrocodone and levorphanol.

[0022] The first step involved in the N-Demethylation of an N-methylmorphinane is the treatment of the N-methyl compound with a suitableoxidizing agent to form the N-oxide. Exemplary oxidizing agents includehydrogen peroxide, m-chloroperbenzoic acid, peracetic acid and magnesiummonoperpxyphthalate. Preferably the oxidising agent is added in a molarexcess, for example about 1.5-5 equivalents, more preferably at leastabout 3 equivalents. The reaction may be carried out at any suitabletemperature which will allow the desired oxidation to proceed, however,ambient temperature, such as about 20-30° C. is preferred in order toavoid additional costs associated with cooling or heating. The reactionis carried out for a time to achieve the desired conversion and maydepend on the amount of material being treated, the amount of oxidisingagent present and the temperature at which the reaction is carried out.Monitoring the reaction by a chromatographic means, such as thin layerchromatography (TLC) will allow the skilled practitioner to determine asuitable time. Suitably, the oxidation reaction is carried out for atleast 30 minutes, such as at least 1 or 2 hours.

[0023] The resulting oxide, can then be treated with a suitable reducingagent. Exemplary reducing agents include Fe(II) based agents such asFeSO₄, FeCl₂ or Fe-porphrin complexes. Preferably the reduction iscarried out at less than ambient temperature, for example, <10° C. Thereaction can be monitored by TLC to determine a suitable the reactiontime. The reducing agent may be added in any amount from a catalyticamount to a molar excess.

[0024] In a preferred embodiment, the reduction step can be effectedwith a catalytic amount of a reducing agent. This is advantageous as anexcess of Fe (II) species can result in handling difficulties byformation of thick emulsions during the reaction work-up steps. Use ofcatalytic amount of Fe(II) compound is also more cost effective in anindustrial process.

[0025] In an embodiment of this demethylation process, the oxidation andreduction steps can be carried out in one step using a biphasic system,in which the oxidation step can take place in one phase (eg organicsolvent) and the reduction steps can take place in the second phase (egaqueous phase).

[0026] Once the N-methyl group has been removed, if desired, anappropriate non-methyl N-substituent (R) can be introduced using methodsknown in the art. Accordingly the present invention provides a method ofconverting an N-methyl morphinane to a non-methyl N-substitutedmorphinane comprising:

[0027] demethylating said N-methyl morphinane as described above;

[0028] treating the demethylated morphinane with a compound of formulaR-L, where R is a non-methyl substituent and L is a leaving group, undersuch conditions such that the nitrogen of the morphinane is substitutedwith R.

[0029] An example of such a treatment would be treatment ofN-demethylated compound with R—Br and a base such as K₂CO₃. Exemplary Rgroups include C₂₋₆alkyl, such as straight chain, branched and cyclicisomers of ethyl, propylbutyl, isobutyl, pentyl, (all isomers), hexyl(all isomers), cyclopropylmethyl (as found in (5), buprenorphine), andcyclobutylmethyl (as found in nalbuphine and butorphanol), C₂₋₆alkenylresidues such as allyl (as found in nalorphine and (6)) and C₂₋₆alkynyl,such as propargyl.

[0030] Examples of leaving groups include halogen, such as Br, Cl and I,mesylate tosylate and triflate.

[0031] As described above the preparation of 14-hydroxy opiates, such as(5) and (6), and orvinols, such as (7), require the incorporation of6,8-diene system into the tetracyclic framework of the formula (A),rather than the Δ⁷-system of morphine and codeine. As described earlier,this has in the past been achieved through use of excess (about 25equivalents) γ-MnO₂. However, the presence of excess MnO₂ has been foundto hinder the recovery of the oxidised product.

[0032] It has now been surprisingly found that the recovery of oxidisedproduct can be increased by treating the product, or the solid MnO₂separated from the reaction medium, with a glycol, glycol ether, orderivative thereof, and/or an inorganic salt. This procedure simplifiesand enhances the recovery and isolation of the desired 6,8-diene fromthe reaction mixture.

[0033] Accordingly, another aspect of the present invention provides amethod for oxidising a Δ⁷-morphinane compound to a Δ⁶,Δ⁸-morphinanecompound, comprising the steps of treating said Δ⁷-morphinane withγ-MnO₂ for a time and under conditions sufficient to oxidise saidΔ⁷-morphinane, and treating the γ-MnO₂ with glycol or a derivativethereof, and/or an inorganic salt.

[0034] Preferably the Δ⁷-morphinane compound, and the Δ⁶,Δ⁸-morphinaneproduct, has oxygen atom substituted A positions 3- and 6-, andpreferably also has an oxygen atom bridging position 4- and 5-.

[0035] Without wishing to be limited by theory, it is believed that theglycol or derivative thereof, the inorganic salt or a combinationthereof acts to displace the Δ⁶,Δ⁸-morphinane product which is bound tothe MnO₂. It is believed that the glycol displaces the product bypreferentially co-ordinating with the manganese species. The salts arealso believed to act in a similar manner, i.e. by reducing the abilityof the manganese to bind the Δ⁶,Δ⁸-morphinane product.

[0036] The glycol or derivative thereof may be any polyoxygenatedalkaline compound capable of displacing the desired Δ⁶,Δ⁸-morphinaneproduct from manganese species present in the reaction medium, orisolated from the reaction medium. Examples of suitable glycols includeethyleneglycol, ethyleneglycol methylether, diethyleneglycol,diethyleneglycol methylether, dipropyleneglycol, dipropyleneglycolmethylether, as well as related allkylene glycols and their derivatives.Preferably the glycol is diethyleneglycol or diethyleneglycolmethylether. Most preferably the glycol is diethyleneglycol. Suitablederivatives include ether derivatives, such as C₁₋₆ alkyl etherderivatives and esters, such as esters of C₁₋₁₂ fatty acids. The spacingof the oxygen atoms of the glycols is preferably such as tosubstantially correspond with the positioning of oxygen atoms of the 3-and 6-positions of the Δ⁶,Δ⁸-morphinane product. Preferably the glycolwill also have an oxygen atom in a position that substantiallycorresponds to the position of the oxygen atom, if present, bridgingpositions 4- and 5- of the Δ⁶,Δ⁸-morphinane product.

[0037] The inorganic salt may be any suitable alkali metal, alkalineearth metal or ammonium salt. The anion may be any suitable anion,including organic anions such as acetate, which forms a salt capable ofdisplacing the desired Δ⁶,Δ⁸-morphinane compound from the manganesespecies present. Examples of suitable anions include halogens, such asbromide, chloride and iodide. A salt should be selected which is solublein the solvent used and which does not interfere with the integrity ofthe product. In some circumstances it is possible to use basic salt,such as NaOH, to induce precipitation or cause other desirable effects,as well as acting as a displacing agent.

[0038] It is also possible to use a combination of the glycol orderivative thereof and an inorganic salt. Preferably diethyleneglycol isused in combination with a mixture of lithium chloride, or sodiumchloride and/or potassium chloride. Most preferably the salts areselected from lithium chloride, sodium chloride and potassium chlorideor a combination thereof.

[0039] The amount of displacing agent used will depend on the amount ofγ-MnO₂ used to perform the oxidation reaction. The amount can be readilycalculated by a person skilled in the art.

[0040] Preferred Δ⁷-morphinane compounds have the formula (8):

[0041] wherein R and R¹ are selected from hydrogen, C₁₋₆alkyl,C(O)C₁₋₆alkyl, benzyl, phenyl or a hydroxy protecting group and R′ ishydrogen, a nitrogen protecting group C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆alkynyl. Suitable nitrogen protecting groups are described in Greene andWutz supra and include C₁₋₆ alkyl and C(O)C₁₋₆alkyl groups. PreferablyR′ is hydrogen or a nitrogen protecting group.

[0042] Preferably, in the oxidation step, an excess of MnO₂ is used.More preferably at least 3 equivalents are used, even more preferably atleast about 5 equivalents are used. The treatment with MnO₂ is carriedout for a time and at a temperature sufficient to achieve the desiredlevel of conversion. The skilled practitioner will be able to determinesuitable conditions by routine methods. Optionally, the mixture may beheated or sonicated to increase the rate of oxidation.

[0043] In order to perform the oxidation the Δ⁷-morphinane willgenerally be dissolved in a conventional non-ionic (ie covalent) solvent(including hydrocarbons, alcohols, nitrites and preferably, ethers suchas diethyl ether or tetrahydrofuran) and a molar excess of MnO₂ added.After the desired reaction period has expired, an appropriate amount ofglycol or derivative thereof and/or inorganic salt (the displacingagent) can be added.

[0044] The displacing agent can be added neat or in a solution oforganic solvent. The solvent selected may be the same or different fromthe solvent used to perform the oxidation reaction. Preferably when aninorganic salt is used, it is first dissolved in a suitable amount oftetrahydrofuran. When used in combination with a glycol, the amount ofsalt is preferably at least a molar equivalent of the amount of glycol.

[0045] The displacing agent will be added to the reaction mixture beforeremoval of the solid γ-MnO₂ residue, or the solid γ-MnO₂ residue can beseparated from the reaction mixture, for example by filtration, and thiscan be separately treated/washed with the displacing agent to releasethe product.

[0046] Preferably, both the N-demethylation step and the MnO₂ oxidationstep, are utilised in the production of Δ⁶, Δ⁸ morphinanes from startingmaterials such as codeine methyl ether (CME), or other compounds, suchas morphine, which are protected at the phenol (3-position) and thealcohol at the 6-position. These may be used as a starting material asit is more useful for transformation to synthetically value addedproducts such as buprenorphine which do not require a methyl group atthe 3-position. N-Demethylation of CME, or other adequately protectedN-methyl morphinane can then be carried out with subsequent protectionof the resulting secondary amine with the desired or appropriate Rgroup. Oxidation of the Δ⁷ system to a Δ⁶, Δ⁸ system can then beeffected in order to provide a diene system available for furthermanipulation to compounds produce the 14-hydroxy opiates such asnaloxone, naltrexone and nalbuphine; and orvinols such as buprenorphineand etorphine by known methodology (see for example the references citedin The Merck Index, 12^(th) Edition, S. Budavari Ed., Merck & Co., Inc.,Whitehouse Station N.J. (1996) for the synthesis of many knowncommercially important morphinanes; GB Patent No. 939 287 (1963) for thesynthesis of naloxone; U.S. Pat. No. 3,332,950 (1967) for the synthesisof naltrexone; GB Patent No. 1 119 270 (1968) for the synthesis ofnalbuphine; GB Patent No. 1 136 214 (1968) for the synthesis ofbuprenorphine; and GB Patent No. 937 214 (1963) for the synthesis ofetorphine). An example of such a process is schematically depicted inScheme (I). Although Scheme (I) depicts the N-demethylation step asbeing carried out first, it will be recognised that access to 14-hydroxyopiates and orvinals can also be achieved by first installing the6,8-diene system and then demethylating.

[0047] Scheme 1: (i) m-CPBA or H₂O₂ then Fe(II)Salt, (ii) R—Br, K₂CO₃;(iii) MnO₂ with displacing agent; (iv) See GB 1 136 214 and GB 939 287supra.

[0048] Throughout this specification and the claims which follow, unlessthe context requires otherwise, the word “comprise”, and variations suchas “comprises” and “comprising”, will be understood to imply theinclusion of a stated integer or step or group of integers or steps butnot the exclusion of any other integer or step or group of integers orsteps.

[0049] Those skilled in the art will appreciate that the inventiondescribed herein is susceptible to variations and modifications otherthan those specifically described. It is to be understood that theinvention includes all such variations and modifications which fallwithin the spirit and scope. The invention also includes all of thesteps, features, compositions and compounds referred to or indicated inthis specification, individually or collectively, and any and allcombinations of any two or more of said steps or features.

[0050] The invention will now be described with reference to thefollowing examples which are intended only for the purpose ofillustrating certain embodiments of the invention and are not to betaken as limiting the generality herein described.

EXAMPLES Example 1 Codeine Methyl Ether N-oxide

[0051] Codeine methyl ether (CME) (1 g 3.2 mmol, MW=313.4) was dissolvedin dichloromethane. m-Chloroperbenzoic acid (50-60%, −3.5 mmol) wasadded in portion and the reaction was allowed to stir for 2 hours.Concentrated ammonium hydroxide (10 mL) was added and the solution wasextracted with chloroform (5×20 mL). Drying and evaporation of thechloroform layer gave 1.16 g of crude product.

Example 2 Norcodeine Methyl Ether

[0052] The N-oxide (200 mg, 0.6 mmol, MW=329.4) in methanol (5 mL) wascooled to <10° C. on an ice bath. Iron(II)sulphate (340 mg) was addedand the reaction was stirred for 2 hours. TLC (CHCl₃:MeOH, 9:1) showedthat the starting material was consumed. After the addition of ammoniumhydroxide (1 mL, 28%) and methanol (20 mL), the solution was filteredthough celite and washed with chloroform (2×20 mL). The solvent wasevaporated under reduced pressure and the crude products were purifiedby column chromatography (CHCl₃:MeOH:NH₃, 9:1:0.1). This yielded 38 mg(20%) of CME (MW=313.4) and 151 mg (83%) of norCME (MW=299.4).

Example 3 γ-MnO₂ Oxidation of CME

[0053] Codeine methyl ether (CME) (500 mg, 1.6 mmol) was reacted withγ-manganese (II) oxide (3.5 g, 25 equivalents) in dry tetrahydrofuran(TFH) for 36 hours at room temperature. Thin layer chromatography showedcomplete conversion of CME to thebaine. 150 mmol total of a 1:1:1mixture of LiCl, NaCl, KCl in 50 mL H₂O was added to the reactionmixture together with diethyleneglycol (5 equivalents based on thetheoretical amount of thebaine). The reaction mixture was filtered andthe reaction product isolated by <how> to afford a yellow foam (496 mg).Pure thebaine was obtained after column chromatography usingchloroform/acetone/methanol/ammonia (15:2:2:0.2) as an eluent. Theunoptimised yield of the thebaine was 75%.

Example 4 Testing of Different Work up Procedures for Isolating Thebaine

[0054] (a) A salt solution (comprising 15 mL of sat. LiCl in THF, 15 mLof sat. NaCl in THF and 15 mL of sat. KCl in THF) was added to the boundthebaine. The mixture was stirred at room temperature overnight and thenfiltered through Celite to remove the manganese oxides. The Celite waswashed with acetone (200 mL) to ensure complete recovery of opiate.After evaporation in vacuo, the residue was reconstituted with water(100 mL) and extracted with chloroform (3×50 mL) and dichloromethane(3×50 mL). The organic extracts were separated, combined and evaporated(first on the rotorary evaporator and then under high vacuum {˜1 mmHG}).After this process, 572 mg of crude thebaine was obtained as a yellowgummy foam.

[0055] (b) 250 mmol total of a 1:1:1 mixture of LiCl, NaCl, KCl in 50mil H₂O were added to the bound thebaine and the mixture was treated aswith work up (a). This afforded 437 mg of crude thebaine as a yellowfoam.

[0056] (c) 250 mmol total of a 1:1:1 mixture of LiCl, NaCl, KCl in 50 mlH₂O was added to the bound thebaine together with diethyleneglycoldimethylether (5 equiv. based on thebaine). The mixture was worked up asin (a) to afford 540 mg of crude thebaine as a yellow foam. 1H NMR shows20% residual diethyleneglycol dimethylether present, therefore 433 mg ofrecovered opiate.

[0057] (d) 250 mmol total of 1:1:1 mixture of LiCl, NaCl, KCl in 50 mlH₂O was added to the bound thebaine together with diethyleneglycol (5equiv. based on thebaine). The mixture was worked up as in (a) to afford642 mg of crude thebaine as a yellow foam. It was difficult to determinethe amount of diethyleneglycol present in 1H NMR. However from bindingstudies previously done would expect 3.5-4 equiv. of diethyleneglycol tobind to surface. Therefore there is 1-1.5 equiv. of diethyleneglycol notbound and present in residue. This is calculated as 100-150 mg, whendeducted from the mass isolated then 500-550 mg is opiate crude.

1. A method for N-demethylating an N-methyl morphinane comprising thesteps of: (i) treating said N-methyl morphinane with an oxidising agentto form the N-oxide morphinane; and (ii) treating said N-oxidemorphinane with a reducing agent.
 2. A method according to claim 1wherein the N-methyl morphinane is selected from compounds of formulae(i), (ii) and (iii):

wherein R and R¹ are independently a hydroxy, methoxy or ethoxy group R²and R³ together form a carbonyl or a ═CH₂ group, R⁴ is hydrogen and R⁵is hydrogen or a hydroxy group and

is an optional double bond; or R² is methoxy or hydroxy, R³ and R⁵together form an ethylene or ethenyl group and R⁴ is a hydroxy orketo-substituted straight or branched C₁₋₆ alkyl group; or a protectedderivative thereof.
 3. A method according to claim 1 wherein theN-methyl morphinane is selected from morphine, codeine, codeine methylether, ethyl morphine (dionine), thebaine, oripavine, oxymorphone,heroin, 14-hydroxy codeinone, dihydrocodone, oxycodone, pholcodeine,etorphine, dihydromorphine, hydromorphone, hydrocodone and levorphanol.4. A method according to claim 1 wherein the oxidising agent is selectedfrom hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid andmagnesium monoperpxyphthalate.
 5. A method according to claim 1 whereinthe oxidising agent is added in a molar excess.
 6. A method according toclaim 5 wherein at least three molar equivalents of oxidising agent isadded.
 7. A method according to claim 1 wherein the reducing agent is anFe(II) based reducing agent.
 8. A method according to claim 7 whereinthe Fe(II) based reducing agent is selected from FeSO₄, FeCl₂ andFe(II)-porphyrin complexes.
 9. A method according to claim 1 wherein thereducing agent is added in a catalytic amount.
 10. A method according toclaim 1 wherein the oxidation and reduction steps are carried out in abiphasic system, in which the oxidation step takes place in one phaseand the reduction step takes place in the second phase.
 11. A method ofconverting a N-methyl morphinane to a non-methyl N-substitutedmorphinane comprising: demethylating said N-methyl morphinane inaccordance with the method of claim 1 and treating the demethylatedmorphinane with a compound of formula R-L where R is a non-methylsubstituent and L is a leaving group, under such conditions such thatthe nitrogen of the morphinane is substituted with R.
 12. A methodaccording to claim 11 wherein R is selected from C₂₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl.
 13. A method according to claim 12 wherein Ris selected from ethyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl,allyl and propargyl.
 14. A method according to claim 11 wherein L isselected from halide, tosylate, mesylate and triflate.
 15. A method foroxidising a Δ⁷-morphinane compound to a Δ⁶,Δ⁸-morphinane compound,comprising the steps of treating said Δ⁷-morphinane with γ-MnO₂ for atime and under conditions sufficient to oxidise said Δ⁷-morphinane, andtreating the γ-MnO₂ with glycol or a derivative thereof, and/or aninorganic salt.
 16. A method according to claim 15 wherein the glycol orderivative is selected from ethyleneglycol, ethyleneglycol methylether,diethyleneglycol, diethyleneglycol methylether, dipropyleneglycol ordipropyleneglycol methylether.
 17. A method according to claim 15wherein the Δ⁷-morphinane compound has oxygen atoms substituted at the3- and 6-positions.
 18. A method according to claim 17 wherein theΔ⁷-morphinane compound has an oxygen atom bridging the 4- and5-position.
 19. A method according to claim 15 wherein the glycol isdiethylene glycol.
 20. A method according to claim 15 wherein theinorganic salt is a salt of an alkali metal, alkaline metal or ammoniumcation.
 21. A method according to claim 15 wherein a glycol is used incombination with an inorganic salt.
 22. A method according to claim 15wherein the Δ⁷-morphinane compound is a compound of formula (8):

wherein R and R¹ are selected from hydrogen, C₁₋₆alkyl, C(O)C₁₋₆alkyl,benzyl, phenyl or a hydroxy protecting group and R′ is hydrogen, anitrogen protecting group C₁₋₆ alky, C₁₋₆ alkenyl, or C₁₋₆ alkynyl.Suitable nitrogen protecting groups are described in Greene and Wutzsupra and include C₁₋₆ alkyl and C(O)C₁₋₆alkyl groups. Preferably R′ ishydrogen or a nitrogen protecting group.
 23. A method according to claim22 wherein R¹ is hydrogen or a nitrogen protecting group.
 24. A methodaccording to claim 15 wherein the inorganic salt is lithium, chloride,sodium chloride, potassium chloride or a combination thereof.
 25. Ademethylated N-methyl morphinane prepared in accordance with the methodof claim
 1. 26. A non-methyl N-substituted morphinane prepared inaccordance with the method of claim
 11. 27. A Δ⁶,Δ⁸-morphinane compoundprepared in accordance with the method of claim
 15. 28. A method ofclaim 15 wherein the Δ⁷-morphinane is a demethylated N-methyl morphinaneof claim 25.